Developmental adaptation of the mouse cardiovascular system to elastin haploinsuffliciency
Developmental adaptation of the mouse cardiovascular system to elastin haploinsuffliciency
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DOI：
10.1172/jci200319028
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Mecham, RP
中科院分区：
文献类型：
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作者：
Faury, G;Pezet, M;Mecham, RP
主动脉瓣上狭窄是一种常染色体显性遗传的弹性蛋白（Eln）功能不全的疾病，由功能缺失突变或基因缺失引起。最近，我们在小鼠（Eln（+/-））中模拟了这种疾病，发现Eln单倍不足导致心血管血流动力学和动脉壁结构的意外变化。发现Eln（+/-）动物从出生起就具有稳定的高血压，平均动脉压比其野生型对应物高25-30 mmHg。这些动物只有中度的心脏肥大，并且过着正常的生活，没有明显的退行性血管疾病的迹象。动脉机械性能的检查表明，在任何给定的血管内压力下，Eln（+/-）动脉的内径通常小于野生型动脉。然而，因为Eln（+/-）小鼠是高血压的，所以有效动脉工作直径与血压正常的野生型动物相当。生理学研究表明，肾素-血管紧张素系统在维持高血压状态中的作用。人类和小鼠的高血压与弹性蛋白单倍不足的关联强烈表明，弹性蛋白和弹性纤维的其他蛋白质应被认为是原发性高血压的致病基因。
Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln(+/-)) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln(+/-) animals were found to be stably hypertensive from birth, with a mean arterial pressure 25-30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln(+/-) arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln(+/-) mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic Fiber should be considered as causal genes for essential hypertension.